The overall goal of this research program is to understand the mechanism of signal transduction mediated by MAP kinase scaffold complexes in mammalian cells. A focus of this study is the c-fun NH2-terminal kinase (JNK) group of MAP kinases. Many of the components of the JNK protein kinase cascade have been identified by molecular cloning and have been characterized in biochemical studies. However, an understanding of the molecular mechanism of signal transduction in vivo has remained elusive. The long-term goal of this research is to define physiologically relevant signaling mechanisms that are employed to regulate the JNK MAP kinase signaling cascade in vivo. Recently, we have identified JIP1 as a protein that functions as a scaffold for the assembly of components of the JNK MAPK signaling pathway. JIP1 binds selectively to JNK and also to a MAPKK (MKK7), to a MAPKKK (MLK protein kinases), and to a Ste20 protein kinase (HPK1). Binding to JIP1 facilitates JNK activation by this protein kinase signaling cascade. A specific focus of this proposal is to define the functional significance and mechanism of action of this JIP-mediated signal transduction pathway. Achievement of the goals of this proposal will increase understanding of the molecular mechanism of MAP kinase signal transduction in vivo. This information represents a basis for the design of novel therapeutic strategies for the treatment of: 1) inflammation; and 2) proliferative diseases such as psoriasis and cancer. The Specific Aims of this proposal are to examine: 1. The physiological role of JIP scaffold proteins. 2. The structure and dynamics of JIP scaffold complexes. 3. The mechanism of JIP-stimulated JNK activity.